Abstract CD38 is a multifunctional surface glycoprotein with crucial roles in autoimmunity, infection, metabolic disease and cancer, including clinical prognostic value. CD38 acts as a receptor and as an ectoenzyme regulating the hydrolysis of Nicotinamide Adenine Nucleotide (NAD+) and the synthesis/hydrolysis of cyclic ADP-ribose (cADPR). CD38 is highly conserved in phylogeny and is expressed by multiple hematopoietic lineages, including B cells, T cells, NK cells, monocytes, macrophages and dendritic cells. Global CD38 deficiency suppresses the Experimental Autoimmune Encephalomyelitis (EAE) animal model of Multiple Sclerosis (MS), an inflammatory disease of the central nervous system (CNS) resulting in neurologic disability in 1 million Americans. However, the broad cellular spectrum of CD38 expression and the lack of conditional CD38 knock-out (cKO) models has not allowed to define the cell or mechanism responsible for CD38 loss-of-function effects. Dissecting the cellular targets responsible for CD38 loss-of-function therapeutic effects would fill this gap and benefit patients by informing the design of adequately targeted therapies. Both lymphoid cells such as T/B cells and mononuclear phagocyte (MP) cells such as macrophages play critical roles in MS and could mediate the pathogenic effects of CD38. Interestingly, our laboratory recently identified CD38 as a selective marker of mouse and human inflammatory macrophages (M1) that promote CNS damage. We hypothesize that MP CD38 expression confers pathogenic phenotype to macrophages and promotes clinical EAE disease. In support of this hypothesis, our preliminary data show increased CD38 expression in MP during EAE and a positive link between MP CD38+ expression and EAE severity. To define the contribution of myeloid CD38 to CNS autoimmunity, we propose to (1) generate an innovative CD38 floxed mouse model to conditionally delete CD38 in specific cell types such as MP cells and (2) address the impact of MP cell CD38+ during EAE development. These models and findings will provide resources of broad research impact and define MP CD38+ cells as a relevant therapeutic target in MS. Beyond MS, CD38 also plays crucial roles in infection, cancer and aging. Therefore, the tools and scientific understanding stemming from this work are expected to have broad basic and translational research impact.